A number of short (ca. 50 amino acid residues or fewer) linear or cyclic cytotoxic peptides have been isolated recently from a variety of sources. These include mellitin, from bee venom, the magainins, from frog skin, and cecropins, from insects (Maloy, et al., Biopolymers (Peptide Science) 37 : 105-122 (1995)). Although of widely varying peptide sequences and structures, these peptides all contain multiple lysine and arginine residues, and, at physiological pH, carry a net positive charge. They also form amphipathic structures wherein one portion of the structure is hydrophilic while the other portion is hydrophobic.
The peptides appear to act solely by direct lysis of the cell membrane (Maloy et al., supra (1995)). In the current model, cell lysis is initiated by the electrostatic attraction of the positive charge on the peptide to the negative phosphate head groups at the exterior surface of the membrane phospholipid bilayer. This interaction leads to insertion of the hydrophobic portion of the protein into the membrane, thereby disrupting the membrane structure. The lytic peptides are, in general, more active against prokaryotic cells, such as bacteria and fungi, than eukaryotic cells. This has led to interest in these peptides as potential agents for the treatment of infections in humans (Maloy et al., supra (1995); Arrowood et al., J. Protozool. 38 : 161S-163S (1991); Haynie et al., Antimicrob. Agents Chemotherapy 39 : 301-307 (1995).
The natural cytotoxic peptides, however, suffer from several disadvantages with respect to their use as human therapeutic agents. First, it appears that these peptides have evolved to act at high concentration at specific localized sites. Thus, when administered as a drug, the dosage necessary to attain an effective concentration at site of infection can be prohibitively high. A second disadvantage is the difficulty of isolating useful amounts of these peptides from the natural sources, along with the high cost of synthesizing useful amounts of peptides in this size regime. Finally, these compounds, like other peptides, are degraded in the gastrointestinal tract, and, thus, cannot be administered orally.
There is a need for anti-microbial agents which possess the broad activity spectrum of the natural cytotoxic peptides, but are inexpensive to produce, can be administered orally and have lower concentration requirements for therapeutic activity.